Abstract

Background and Purpose—Hematoma expansion after acute intracerebral hemorrhage is common and is associated with early deterioration and poor clinical outcome. The computed tomographic angiography (CTA) spot sign is a promising predictor of expansion; however, frequency and predictive values are variable across studies, possibly because of differences in onset-to-CTA time. We performed a patient-level meta-analysis to define the relationship between onset-to-CTA time and frequency and predictive ability of the spot sign.

Methods—We completed a systematic review for studies of CTA spot sign and hematoma expansion. We subsequently pooled patient-level data on the frequency and predictive values for significant hematoma expansion according to 5 predefined categorized onset-to-CTA times. We calculated spot-sign frequency both as raw and frequency-adjusted rates.

Introduction

Intracerebral hemorrhage (ICH) causes the majority of stroke morbidity and mortality.1,2 Although ICH volume and location are strong predictors of outcome, neither are modifiable at the time of diagnosis.3,4 However, hematoma expansion occurs in ≤40% of patients, worsens outcome, can potentially be prevented,5–8 and is therefore a therapeutic target of ongoing clinical trials (NCT00810888, NCT01359202, NCT01702636, and ISRCTN93732214).

Attempts to mitigate hematoma expansion failed to demonstrate improved outcomes in large randomized controlled trials.7,9,10 This is partially attributed to the challenge of accurately identifying patients most likely to benefit from interventions targeting hematoma expansion.11 To date, only one trial demonstrated a shift toward reduced disability with blood pressure lowering, which was achieved with a marginal reduction in hematoma expansion.12 We can potentially increase the absolute effect of such therapies by using biomarkers to identify patients at highest risk of this expansion. Contrast extravasation after computed tomographic angiography (CTA), termed the spot sign, is a promising radiological marker that predicts hematoma expansion.13–24

The spot sign is appealing to clinicians and researchers because CTA is a rapid and noninvasive imaging modality used in acute stroke.25,26 However, the predictive performance of the spot sign is highly variable across studies, with positive predictive values (PPV) ranging from 0.22 to 1.00.27 Although preliminary data suggests that onset-CTA time may explain some of this variability,28,29 the relationship remains unclear. We, therefore, performed a systematic review and patient-level meta-analysis to assess the frequency and predictive performance of the spot sign in relation to onset-to-CTA times in patients presenting with acute ICH.

Methods

With the assistance of an experienced health sciences librarian (L.-A. Ufholz), we searched MEDLINE (1946 to present), EMBASE (1974 to present), Cochrane Central Register of Controlled Trials (CENTRAL), and The Cochrane Library Database of Systematic Reviews (latest issue) for ICH studies reporting the CTA spot sign. We did not restrict the search by language, date, or study type. We registered the search strategy with the University of Ottawa, which is available at http://hdl.handle.net/10393/30685. The search was completed in November 2012 and was updated in September 2013. Additional references were identified from the bibliographies of retrieved articles and by contacting the authors of retrieved articles. Two authors (D. Dowlatshahi and M. Sharma) independently assessed all potential studies identified by the search strategy. Studies that reported CTA assessment of patients with acute primary ICH and initial and follow-up hematoma volumes were included. Review articles and duplicate publications were excluded. Disagreements about inclusion were adjudicated by consensus.

We contacted corresponding authors of all included studies to request patient-level data using a standard data collection form. We requested demographic information, medical history, spot-sign status (spot positive or spot negative), baseline and follow-up hematoma volumes, and time from onset to presentation and CTA. We a priori categorized onset-to-CTA time into the following 5 time strata: <120 minutes, 120 to 239 minutes, 240 to 359 minutes, 360 to 479 minutes, and >480 minutes. Stroke onset time was either a witnessed onset or a last seen well time that could be classified into the 5 strata. To ascertain the risk of bias in eligible studies, 2 reviewers independently determined the adequacy of inclusion criteria, clinical and time of onset data, scanning intervals and technique, hematoma measurement technique, and selective outcome reporting. Contributing studies were approved by their local institutional research ethics boards.

Statistical Analysis

We compared the baseline characteristics of included and excluded patients using Fisher exact test, t test, and Mann–Whitney U-test as appropriate. We assessed the heterogeneity of proportions by study and by time strata (I2). We calculated the overall frequency of spot sign from all patients with baseline CTA and noncontrast computed tomography (NCCT) and reported both raw and frequency-adjusted rates (means weighted by total N). Similarly, we reported absolute hematoma growth and proportion of patients with significant hematoma growth from all patients with baseline CTA, baseline NCCT, and follow-up NCCT. We defined significant hematoma expansion as an increase of 6 mL or 33% in parenchymal hematoma volume between baseline and follow-up NCCT17,24,30,31 and calculated sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and the area under the curve (AUC) for the spot sign as a predictor of significant hematoma expansion. We modeled the probability of ICH growth over time, stratified by the spot sign. We used a logistic regression model with time and spot-sign status as covariates and estimated the predicted probabilities of ICH growth in each stratum. We used SPSS v20 (IBM, Armonk, NY) and STATA (College Station, TX) for all analyses.

Results

We identified 2051 potential studies in our search of which 11 met our inclusion criteria (Table 1). A 12th study was identified by bibliography review.20 Of these, we were able to obtain patient-level data on 8 studies, and to minimize risk of reporting bias, we obtained the full data set from the authors (N=1343). Spot sign status was identified by the local investigators in all studies and was considered to be present if high-density contrast material or foci of enhancement was seen within the hematoma without connection to outside vessels.24,27,34 All studies included first-pass CTAs except one, which included both first and second pass CTA.23 Hematoma volume was measured in the 8 studies with available data by either computer-assisted planimetry (3 studies)17,19,23 or the ABC/2 method (5 studies).14,16,22,24,32

Systematic Review Results and Patient-Level Data Available for Meta-Analysis

Of the 1343 patients, 44 did not have a baseline computed tomography scan, 3 did not have spot sign assessment, and 120 could not be classified into time strata because of incomplete time of onset or last seen well information. We were able to obtain baseline hematoma volumes, spot sign status, and time-to-CTA for 1176 patients, which formed the spot-sign frequency cohort, and had follow-up hematoma volumes for 1039 patients for the hematoma expansion cohort. Patients excluded because of incomplete data were older (mean age 75 versus 67 years), more likely to be female, found to use antiplatelets, found to have lower hemoglobin and higher baseline glucose, and found to have larger hematoma volumes (Table 2). The median time to follow-up NCCT was 22.8 hours (interquartile range 8.7) for spot-negative patients and 22.9 hours (interquartile range 8.8) for spot-positive patients.

There was significant heterogeneity of spot-sign frequency between studies (I2=20.67; P=0.004), and this was because of heterogeneity in the 0- to 2-hour strata (I2=15.5; P=0.016) and the 2- to 4-hour strata (I2 = 16.5, P=0.011). There was no heterogeneity by study observed at the later time strata. The frequency of the spot sign was 26% for the group as a whole and showed a significant relationship with onset-to-CTA time strata (P<0.001), decreasing from 39% within 2 hours of onset to 13% after 8 hours (Figure 1).

There was no heterogeneity in hematoma expansion between studies (F=0.45; P=0.87) or time strata (F=0.75; P=0.56). In all time intervals, the median volume of hematoma expansion was greater for spot-positive as compared with spot-negative patients, but there was no demonstrable decrease in median hematoma expansion by time strata in spot-positive patients (overall model F=1.28; P=0.14; Table I in the online-only Data Supplement). However, there was a decreasing relationship between spot positivity and significant hematoma expansion (≥6 mL or ≥33%) as onset-to-CTA time strata increased (Figure 2; Table II in the online-only Data Supplement). Furthermore, sensitivity and PPV of the spot sign to predict significant hematoma expansion was greatest in the earlier time strata, whereas the specificity and negative predictive value of spot sign increased with time (Table 3).

Modeled probability of significant intracerebral hemorrhage (ICH) growth as a function of time from onset to computed tomographic angiography (CTA). The probability of ICH growth over time was stratified by the spot sign using a logistic regression model with time and spot-sign status as covariates. The inset shows a population restricted to early imaging times.

Discussion

We performed a large patient-level meta-analysis and found significant variation in the frequency and predictive value of the CTA spot sign based on onset to CTA time. Frequency of spot sign decreased to a third of its value between the earliest (0–2 hours) and latest (>8 hours) onset to scan times. The sensitivity and PPV of the spot sign to predict hematoma expansion was similarly highest in early time strata. Although the CTA spot sign is a promising radiological biomarker for prognostication and patient selection for emerging ICH therapies, the onset-to-imaging time should be considered when attempting to identify patients at highest risk for hematoma expansion.

Our study provides important data to optimize patient selection in ongoing clinical trials and offers frequency and performance data to inform future trial design. However, we also highlight the limitations of the spot sign: the best sensitivity to detect hematoma expansion was achieved in the first 2 hours from symptom onset and was only 60%. This modest predictive performance precludes the use of the spot sign in isolation and argues for its inclusion into expansion prediction scores. By explaining the variability by time in spot sign performance, our study allows for the refinement of emerging ICH expansion scores and the future development of clinical prediction rules.31,35,36 Furthermore, we highlight that even in the best-case scenario where patients present hyperacutely, 40% of those destined for hematoma expansion will not be identified by the spot sign, which supports the need for prediction rules that do not solely rely on CTA.35 Conversely, our data suggests that in later time points, the spot sign has a high specificity and negative predictive value, which may reassure treating clinicians and clinical trialists that spot-negative patients presenting after 6 hours likely have stable hematomas.

Our findings are consistent with the presumed underlying pathology of the spot sign as the source of ICH and help unify existing theories around its pathophysiology. A recent dynamic CTA study revealed that early spot signs behave in a manner consistent with active extravasation.15 But as time goes on, endogenous hemostatic mechanisms ultimately stop the bleeding. In the classical ICH pathology series, Dr Fisher discussed bleeding globes consisting of concentric fibrin rings attached to the walls of parenchymal hematomas.37 These 100- to 200-μm globes were thought to be thrombosed sites of vascular rupture and, because they fall within the spatial resolution of CTA, are likely a pathological equivalent to the spot sign.24 But these autopsy samples would have been acquired many hours after ICH onset, by which time the formation of stable fibrin globes around a ruptured vessel would have reduced the chance of ongoing bleeding; if imaged, these would likely be spot-positive yet unlikely to expand. The onset to CTA time relationship in our study fits with the hypothesis that the radiological spot sign initially represents a site of vessel rupture. Indeed, a recent pathological report demonstrated a focal vessel disruption in a spot-positive patient undergoing hematoma evacuation.38 We hypothesize that over time the vessel disruption thromboses forms concentric fibrin rings and ultimately achieves hemostasis. Nevertheless, this explanation for late spot sign is speculative; it is entirely possible that late spot signs may also represent active extravasation, albeit at a lower rate.

The major strength of this study is the availability of patient-level data from different studies. However, there are several important limitations. Among other missing data, we did not have access to clinical outcome data from all studies and restricted our analysis to radiological outcomes only. We were also unable to access patient-level radiological data from 4 studies identified in our review representing 563 patients,18,20,21,33 which may have introduced a bias. But we note that the PPV was reported in one of these studies,18 and it was found consistent with our current findings. There have also been additional spot sign publications since our initial search strategy.39 This was unavoidable because of the prolonged timelines required to acquire regulatory approvals necessary for access to patient-level data, particularly across national jurisdictions. A second limitation to our study is the different techniques used to measure hematoma volumes. Although this can contribute to variability in absolute volumes,40,41 it is less likely to affect the dichotomous hematoma expansion cut-offs (6 mL or ≥33%). The third limitation is the relatively low number of spot-positive patients in later time windows. Although this may increase variability in point estimates at later time points, the finding of low spot-sign prevalence design is in line with previous studies29 and is nevertheless useful for future studies. A fourth limitation is the different CTA techniques used throughout the different studies included in this analysis, and we cannot exclude the possibility that in some cases, there may have been delays between NCCT and CTA which may contribute to heterogeneity. Finally, we found that patients with incomplete data had markers of poor outcome, such as advanced age and increased glucose and hematoma volumes; it is possible that our estimates of hematoma expansion may be conservative because of their exclusion.

Conclusions

We demonstrate that spot-sign frequencies decreased as onset to scan times increase. Although the spot sign remains predictive of hematoma expansion in delayed presentations, PPV and sensitivity decrease and negative predictive value and specificity increase as time-to-CTA increases. Furthermore, the overall performance of the spot sign is modest, suggesting the need for additional clinical and radiological factors to predict hematoma expansion. Our results open a path for more precise risk stratification for patients with acute ICH and inform ongoing and emerging clinical trials.

Disclosures

Dr Dowlatshahi has a patent pending for computerized automatic detection of contrast extravasation. Dr Goldstein reports grants and personal fees from CSL Behring, both outside the submitted work. Dr Hill sat on boards for the Heart & Stroke Foundation of Alberta/NWT/NU, Institute for Circulatory and Respiratory Health of CIHR, Canadian Federation of Neurological Sciences, provided consultancies for Vernalis Group Ltd and Merck Ltd, has grants from Hoffmann-La Roche Canada Ltd, Covidien, holds stocks in Calgary Scientific inc, and has received speaker honoraria from Servier Canada, BMS Canada; all are unrelated to the current work. Dr Rizos has received consulting and speaking honoraria from BMS Pfizer, Bayer Healthcare, and Boerhinger Ingleheim, unrelated to the current work. Dr Rosand reports portions of the patient-level data were funded by the US National Institutes of Health. Dr Sharma has received consulting and speaker’s honoraria from Boehringer Ingelheim, Bayer, BMS Pfizer, provided consultation for Daiichi Sankyo, unrelated to the current work. All other authors have nothing to disclose.

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